DESCRIPTION The severe bone phenotype in microphtalmia (MITF) mutant mice indicates that the helix-loop-helix (HLH) zipper transcription factor encoded by the microphthalmia (MITF) gene has significant role in terminal differentiation of multi-nucleated osteoclasts. In addition to providing a very interesting system to study developmentally regulated gene expression in a mammalian system, studying the MITF gene may have direct impact on human disease. In particular, osteoporosis in post- menopausal women and the osteolytic bone destruction and hypercalcemia that occurs in patients with multiple myeloma are examples of clinical conditions where this research may have potential impact. The long term goal of this grant are to determine, at the molecular level, the function of the MITF protein in normal osteoclast biology. The specific aims of the proposal are: 1. To determine if MITF is a target of Erk-2 in osteoclasts 2. To determine if MITF is a target of ERK-2 in osteoclasts. 2. To determine if MITF is a target of Jun kinase (JNK) in osteoclasts. These studies will be performed in three experimental systems: heterologous cell lines, primary osteoclast-like cells in vitro and in vivo in mouse transgenic models.